Diabetes mellitus is a systemic disease characterized by disorders in the actions of insulin and other regulatory hormones in the metabolism of carbohydrates, fats and proteins, and in the structure and function of blood vessels. The primary symptom of diabetes is hyperglycemia, often accompanied by glucosuria, the presence in urine of large amounts of glucose, and polyurea, the excretion of large volumes of urine. Additional symptoms arise in chronic or long standing diabetes. These symptoms include degeneration of the walls of blood vessels. Although many different organs are affected by these vascular changes, the nerves, eyes and kidneys appear to be the most susceptible. As such, long-standing diabetes mellitus, even when treated with insulin, is a leading cause of blindness.
There are two recognized types of diabetes. Type I diabetes is of juvenile onset, ketosis-prone, develops early in life with much more severe symptoms and has a near-certain prospect of later vascular involvement. Control of this type of diabetes is difficult and requires exogenous insulin administration. Type II diabetes mellitus, is of adult onset, ketosis-resistant, develops later in life, is milder and has a more gradual onset.
One of the most significant advancements in the history of medical science came in 1922 when Banting and Best demonstrated the therapeutic effects of insulin in diabetic dogs. However, even today, a clear picture of the basic biochemical defects of the disease is not known, and diabetes remains a serious health problem. It is believed that two percent of the United States population is afflicted with some form of diabetes. The introduction of orally effective hypoglycemic agents was an important development in the treatment of hyperglycemia. Oral hypoglycemic agents are normally used in the treatment of adult onset diabetes.
Observations in animal models on glucose metabolism for type II diabetes and in humans suggest that sex steroids play a permissive role in the phenotypic expression of hyperglycemia. These observations have prompted studies on the effects of androgens and estrogens on blood glucose levels. Testosterone administration to intact or ovarectomized female rats resulted in marked insulin resistance which correlated to morphological changes in muscle, Holmang, et al., Am. J. Physiol., 259, E555-560 (1990); Holmang, et al., Am. J. Physiol., 262, E851-855 (1992). In streptozotocin diabetic rats, implanted testosterone antagonized the ability of residual insulin to maintain glycemic control, Leet al., Endocrinology, 116, 2450-2455 (1985). In contrast, glucosuria disappeared in castrated diabetic KK mice and reappeared when androgens were replaced in these mice, Nonaka, et al., Jpn. J. Vet. Sci., 50, 1121-1123 (1988); Higuichi, et al., Exp. Anim., 38, 25-29 (1989).
Results from estrogen administrations also support the hypothesis that the balance between androgens and estrogens is critical to the development of hyperglycemia. Daily estradiol administrations to diabetic KK mice normalized the blood glucose levels and eliminated glucosuria, Toshiro, et al., Jpn. J. Vet. Sci., 51, 823-826 (1989). Estradiol also lowered the blood glucose levels of C57BL/6J-ob/ob mice, Dubuc, Proc. Soc. Exp. Biol. Med., 180, 468-473 (1985) and C57BL/KsJ-db/db mice, Garris, Anatomical Record, 225, 310-317 (1989).
Sexual dimorphism of hyperglycemia was observed in VY/WfL-A.sup.vy /a mice (VY mice, Shafrir, Ed., Lessons From Animal Diabetes, III, 294-299, Smith-Gordon, London (1990); Gill, et al., Life Sci., 48, 703-710 (1991). However, hyperglycemia could be induced by dexamethasone (dex) in female VY mice, Yen, et al., Int. J. Obesity, 16, 923-933 (1992).
The present invention relates to methods of lowering blood glucose levels in mammals by administering to a mammal in need of treatment, an effective amount of an antiestrogen. These compounds may be useful for treating diabetes. Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.